Diabetes results from an imbalance between insulin production by the pancreatic β-cell and insulin action on metabolic tissues such as the liver, fat and muscle. In type 1 diabetes, an autoimmune attack on endogenous cells β results in nearly absolute insulin deficiency, whereas in type 2 diabetes, resistance to the action of insulin is a major component of the pathophysiology. Pancreatic β cells have remarkable ability to compensate for insulin resistance, by increasing insulin synthesis and secretion and by expanding the number of β cells. Therefore, hyperglycemia and the attendant complications of chronic hyperglycemia on the kidney, eye, and heart, causing blindness, kidney failure and heart disease, result only when β cells can no longer compensate due to genetic or environmentally induced insults. Therefore, efforts to understand the development of islet beta cell mass and to promote islet compensation for insulin resistance may lead to successful therapeutic strategies for the treatment of all forms of diabetes.
PDX-1 is a Hox type homeodomain-transcription factor that is pivotally positioned in the transcriptional hierarchy governing β cell development. PDX-1 is expressed in a biphasic manner during embryonic and fetal pancreas development and it plays two critical roles, first in the early development of both the endocrine and exocrine pancreas, and then in the later differentiation of the β cell. Deficiencies in Pdx1/IPF-1 show pancreatic agenesis, whereas heterozygous PDX-1 mutation leads to the development of an initially normal morphological mass of β cells but impaired β cell function, leading later to abnormal glucose tolerance in mice and early-(MODY4) and late-onset forms of type 2 diabetes in humans. PDX-1 is recognized as a transcriptional activator of key islet and β cell specific genes, including insulin, somatostatin, Glut2, and IAPP.
Therefore modulation of PDX-1 presents a potential therapeutic pathway target in the treatment of several pathologies associated with abnormal glucose metabolism.